Certain 2-amino-4,5-bis(p-methoxyphenyl)thiazoles



United States Patent ice 3,458,526 Patented July 29, 1969 3,458,526CERTAIN Z-AMINO-4,5-BIS(p-METHOXY- PHENYL)THIAZOLES Daniel Lednicer,Portage, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., acorporation of Delaware No Drawing. Filed Sept. 26, 1966, Ser. No.581,747 Int. Cl. C07d 91/34, 91/30 US. Cl. 260-3063 13 Claims ABSTRACTOF THE DISCLOSURE There are disclosed Z-aminoand variousZ-hydrocarbylaminoand 2-acylamino-4, S-dianisylthiazoles, 2- alkylandZ-phenylthiazoles, and 4,5-dianisyl-2-thiazo1eacetates, as well asprocesses for making them by the reaction of u-bromodesoxyanisoin withthe appropriate thioamide or thioamide analogues. These compounds areuseful for treating various inflammatory conditions and in certainantiviral applications.

The present invention is directed to novel compounds and is moreparticularly concerned with certain 2-substituted 4,5 dianisylthiazoles[2-substituted-4,5-bis(pmethoxyphenyDthiazoles], certain novelintermediates therefor and the production thereof.

The novel products, intermediates therefor and process thereof can beillustratively represented by the following sequence of Formulae A andB:

wherein R is selected from the group consisting of hydrogen; alkylhaving from 1 to 10 carbon atoms, inclusive; lower alkenyl having from 3to 6 carbon atoms, inclusive; phenyl of the formula:

NH OCH H I a N 4 Q-oom RNC 1 II III U! l R lls -0crn ing from 1 to 10carbon atoms, inclusive, and phenyl defined as above;

and (B) of Br\ /NH: N -0CH= lh-CHz-O upon,

Mil-(Ga e.

CO OH VIII H C L S OCH:

wherein R is selected from the group consisting of hydrogen, lower alkylhaving up to and including 4 carbon atoms, and phenyl, and R is alkylhaving up to and including 2 carbon atoms.

The alkyl group containing from 1 to carbon atoms, inclusive, as used inthe above formulae, comprises the members methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl and the branched isomersthereof. Alkyl groups having less carbon atoms comprise the earlymembers of the same series.

The lower alkenyl in the formulae above comprises allyl, l-methylallyl,Z-methylallyl (methallyl), 2-butenyl (crotyl), B-butenyl,1,2-dimethylallyl, Z-ethylallyl, Z-methyI-Z-butenyl, 3-pentenyl,4-methyl-2-pentenyl, 2-hexenyl, and the like.

The term halogen used as su-bstituent in the phenyl group of phenyl,benzyl and benzoyl substituents comprises fluorine chlorine, bromine andiodine.

The term alkoxy having from 1 to 3 carbon atoms, inclusive comprisesmethoxy, ethoxy, propoxy and isopropoxy.

The term carbalkoxy having from 2 to 4 carbon atoms, inclusive comprisescarbomethoxy, carbethoxy, carbopropoxy, carboisopropoxy, carbobutoxy,and the like.

The term acyl of the formula RCO in which R' is selected from the groupconsisting of .alkyl having from 1 to 10 carbon atoms, inclusive, andphenyl defined as above" comprises acetyl, propionyl, butyryl, valeryl,hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, benzoyl,p-chloro'benzoyl, 2,4-dichlorobenzoyl, ofiuorobenzoyl, miodobenzoyl,2,4-diiodobenzoyl, o-bromobenzoyl, p-methoxybenzoyl, o-ethoxybenzoyl,m-methoxybenzoyl, m-propoxybenzoyl, p-isopropoxybenzoyl,1,3,5-trimethylbenzoyl, m-ethylbenzoyl, p-propylbenzoyl,m-methylbenzoyl, o-methylbenzoyl, m-isopropylbenzoyl, and the like.

The process (A) of the present invention comprises: heating a solutionof a-bromodesoxyanisoin (II) with a selected thiourea (I) to give anovel Z-(amino-substituted)-4,5-dianisylthiazole (III); and treating, ifdesired, a compound of Formula III (when R=H) with an acyl halide inwhich the acyl group is of the formula:

defined as .above, and the halogen of the halide is selected from thegroup consisting of chlorine and bromine, to give a novel compound ofFormula IV.

The process (B) of this invention comprises: heating a solution ofa-bromodesoxyanisoin (II) with a thioamide (V) to give the correspondingZ-alkylor 2-benzyl- 4,5-dianisylthiazole (VI); treating (VI) with alithium alkyl to give the corresponding lithium salt (VII); treating(VII) with carbon dioxide to obtain the corresponding4,5-dianisyl-2-thiazoleacetic acid (VIII), which can be N MHJI h VIIesterified in conventional manner with diazomethane or diazoethane togive the corresponding alkyl 4,5-dianisyl-2- thiazoleacetate (IX).

The novel compounds of the present invention, III, IV, VI and IX,possess high anti-inflammatory activity frequently exceeding that ofphenylbutazone. Illustrativcly, 2-phenylamino-4,5-dianisylthiazole hasapproximately five times the activity of phenylbutazone (measured inrats). These compounds, III, IV, VI and IX, are thus very well suitedfor the treatment of inflammatory diseasees and inflammations ofnon-bacterial origin, such as contact dermatitis, allergic inflammationsand also mastitis in cattle. The compounds of Formulae III, IV, VI andIX, have, moreover, anti-viral activity and can be used for cleaninglaboratory glassware contaminated by virus, as well as for destroyinginfiltration of viral phages into colonies of bacteria raised forexperimental purposes or used for specific chemical tasks.

The novel compounds of Formulae VII and VIII are intermediates for theproduction of the compounds of Formula IX.

The thioureas used in this invention are known to the art, or areproduced as shown in the preparations by the general process of treatinga selected amine with carbon disulfide in the presence of a base liketriethylamine, followed by treatment with ehtyl chloroform-ate, andtreating the thus-obtained isothiocyanate with ammonia to give thecorresponding thiourea.

In carrying out the process of the present invention,a-bromodesoxyanisoin together with the selected thiourea (I) orthioamide (V) is heated in an inert organic solvent such as methanol,ethanol, propanol, acetonitrile and the like. In the preferredembodiment of this invention, the reactants are used in equimolecularquantities, and the reaction, when carried out at reflux temperature,needs for completion between 1 and 5 hours. It is possible, but notadvantageous, to carry out the reaction at lower temperatures withinlonger reaction periods. After the reaction is terminated, the desiredcompound of Formula III or VI is recovered in conventional manner suchas by removing the solvent by distillation or precipitating the productby diluting the solvent with water or with another solvent in which thedesired product is insoluble. The compound can be purified bycrystallization or chromatography.

In the event a 4,S-dianisyl-Z-thiazoleacetic acid (VIII) is desired, aZ-alkylor 2-(phenylalkyl)-4,5-dianisylthiazole (VI) is reacted withbutyllithium at low temperatures in an inert organic solvent. Generallythe 2-alkylor 2- (phenylalkyl)-4,5-dianisylthiazole is in solution,e.g., in tetrahydrofuran, ether, dibutyl ether, or the like, whereas thebutyllithium is in a hydrocarbon solvent which does not solidify at thetemperature of the reaction (-25 to C.) like petroleum ether, n-pentaneor the like.

The thus-obtained lithium salt of 2-alkylor Z-benzyl-4,5-dianisylthiazole (VII) is reacted with carbon dioxide in an inertsolvent such as tetrahydrofuran, ether, dioxane or the like. Theresulting lithium 4,5-dianisyl-2-thiazoleacetate is treated with aqueousacid followed by extraction with a water-immiscible solvent such asether, methylene chloride or the like, and evaporating the solvent. Thethusobtained 4,5-dianisyl-Z-thiazoleacetic acid (VIII) can be esterifiedin conventional manner with diazomethane or diazoethane in ethersolution to give a more stable methyl or ethyl4,5-dianisyl-2-thiazoleacetate (IX).

The following examples and preparations are illustrative of the productsand processes of this invention, but are not to be construed aslimiting.

PREPARATION 1 Decylthiourea A solution of 20 g. of decylamine, 12.95 g.of triethylamine and 110 ml. of methylene chloride was cooled to C.under continuous stirring. To this solution was added, over a period of1 hour, a solution of 7.7 ml. of carbon disulfide in 45 ml. ofchloroform. The mixture was allowed to warm to C. and it was then againcooled in ice. To this mixture was then added 13.9 g. of ethylchloroformate in 23 ml. of chloroform at such a rate as tokeep thetemperature below 4 C. The reaction mixture was then stirred for minutesat room temperature, again cooled in ice, and treated with 12.95 g. oftriethylamine in 23 ml. of chloroform over a period of minutes.Following 40 minutes of stirring at room temperature, the mixture waswashed first with ice-water, then cold 2.5 N hydrochloric acid, icewater and aqueous sodium bicarbonate solution. The organic layer wastaken to dryness and the residual oil was distilled at 0.25 mm. Therewas obtained 21.34 g. of decyl isothiocyanate of boiling point 99103.5C./0.25 mm.

Into a solution of the 21.34 g. of decyl isothiocyanate in 200 ml. oftetrahydrofuran was passed gaseous ammonia during a period of 30minutes. The solution was then heated at reflux for 2 hour-s and takento dryness in vacuo. The residue was recrystallized twice from methanolto give 7.19 g. of decylthiourea of melting point 94-99" C.

Analysis.Calcd. for C H N S: C, 61.05; H, 11.18; N, 12.95. Found: C,61.20; H, 11.28; N, 12.81.

PREPARATION 2 Anisylthiourea phenyl isothiocyanate thus obtained wastwice distilled (once at 1.3 mm. and once at- 0.45 mm.) to give 13.0 g.of pure p-methoxyphenyl isothiocyanate of boiling point 8688 C./'0.45mm.

Into a solution of the p-methoxyphenyl isothiocyanate in ml. of absoluteethanol was passed gaseous ammonia for 30 minutes; a solid precipitatedout of solution. The mixture was allowed to stand overnight at roomtemperature and the solid collected on a filter. Recrystallization ofthe crude anisylthiourea from methanol gave 10.30 g. of anisylthioureaof melting point 208210.5 C.

Analysis.-Calcd. for C H N OS: C, 52.72; H, 5.53; N, 15.38. Found: C,53.28; H, 5.63; N, 15.56.

PREPARATION 3 p-Carbethoxyp'henylthiourea (A) p-CARBETHOXYPHENYLISOTHIOCYANATE A solution of 4 ml. of carbon disulfide in 23 ml. ofchloroform was added to a well stirred solution of 10 g. of ethylp-aminobenzoate and 6.74 g. of triethylamine in 57 ml. of methylenechloride, at -l0 C., and over a period of 40 minutes. After standing atabout 5 to 10 C. for 4 /2 days, a solution of 6.97 g. of ethylchloroformate in 12 ml. of chloroform was added at a rate to keep thetemperature below 4 C. The mixture was then allowed to stir at roomtemperature for 20 minutes. The mixture was again cooled in ice and asolution of 6.73 g. of triethylamine in 12 ml. of chloroform was added.The reaction mixture was then allowed to warm to room temperature andstirred for 40 minutes, then washed with ice water, cold 2.5 Nhydrochloric acid, ice water and aqueous sodium bicarbonate solution.The organic layer was separated and then evaporated to give a solidresidue which was chromatographed with a mixture of 98% Skellysolve Bhexanes and 2% acetone over 600 ml. of Florisil (anhydrous magnesiumsilicate) to give 0.40 g. of p-carbethoxyphenyl isothiocyanate as oilycrystals.

(B) p-CARBETHOXYPHENYLTHIOUREA A solution of 0.40 g. ofp-carbethoxyphenyl isothiocyanate in 3 ml. of tetrahydrofuran wastreated with a solution of 7.3 ml. of 0.26 N ammonium hydroxide intetrahydrofuran. Following 2 hours standing at room temperature, thesolution was evaporated to dryness and the resulting residualcrystalline solid was recrystallized twice from acetone-Skellysolve Bhexanes to yield p-carbethoxyphenylthiourea of melting point 149-151 C.

Arzalysis.--Calcd. for C H N O S: C, 53.55; H, 5.40; N, 12.49; S, 14.29.Found: C, 53.63; H, 5.62; N, 13.15; S, 13.86.

PREPARATION 4 p-Chloro-benzylthiourea In the manner given in Preparation1, 20 g. of p-chlorobenzylamine was reacted with carbon disulfide,triethylamine, and ethyl chloroformate to give upon distillation 14.5 g.of p-chlorophenyl isothiocyanate of boiling point 106107.5 C. at 0.35mm.

This p-chlorobenzyl isothiocyanate was reacted with ammonia intetrahydrofuran to give, after recrystallization fromacetone-Skellysolve B hexanes, 13.45 g. of pchlorobenzylthiourea ofmelting point 136-139 C.

Analysis.Calcd. for C H ClN S: C, 47.87; H, 4.52; N, 13.96; S, 1597.Found: C, 47.88; H, 4.58; N, 13.69; S, 15.82.

In the manner given in Preparation 1, other alkyl-, alkenyl-, phenyl-,benzyl-, and phenyland benzyl-, substituted by halogen, alkyl, alkoxy,carboxy and carbalkoxy, thioureas can be obtained by reacting thecorresponding amines with carbon disulfide in the presence oftriethylamine and thereupon with ethyl chloroformate to give thecorresponding isothiocyanate which after treatment with ammonia givesthe desired substituted thiourea. Representative thioureas, thusproduced, include: propyl thiourea, butylthiourea, isobutylthiourea,pentylthiourea, hexylthiourea, octylthiourea, nonylthiourea,methallylthiourea, crotylthiourea, (2-hexenyl)-thiourea,p-fiuorobenzylthiourea, 2,4-diiodobenzylthiourea, phenylthiourea,isopropylthiourea, benzylthiourea, p-bromophenylthiourea,2,4,6-tribromophenylthiourea, p-chlorophenylthiourea,p-iodophenylthiourea, m-fiuorophenylthiourea, m-fluorobenzylthiourea,p-fluorobenzylthiourea, o-chlorobenzylthiourea, p-ethoxyphenylthiourea,p-propoxybenzylthiourea, and the like.

EXAMPLE 1 Z-amino 4,5-dianisylthiazole A solution of 10.0 g. ofa-bromodesoxyanisoin and 2.30 g. of thiourea in 150 ml. of absoluteethanol was heated at reflux temperature for a period of 3 /2 hours.After the bulk of the solvent was removed in vacuo and the residuetreated with water, a solid precipitated which was recrystallized fromaqueous acetone to give 7.66 g. of 2-amino- 4,5-dianisylthiazole ofmelting point 208 to 211 C.

A small sample was recrystallized from the same solvent to give pure2-amino-4,5-dianisylthiazole of melting point 209-210.5 C.

Analysis.-Calcd. for C H -N O S: C, 65.36; H, 5.16; N, 8.97. Found: C,65.39; H, 5.24; N, 9.05.

EXAMPLE 2 Z-buty[amino-4,5-dianisylthiazole A solution of 1.32 g. ofbutylthiourea and 3.35 g. of a-bromodesoxyanisoin in 50 ml. ofacetonitrile was heated at reflux for a period of 1.5 hours. Thesolution was allowed to cool and the solvent removed in vacuo. Theremaining solid residue was dissolved in ether-methylene chloride andthe solution was washed first with aqueous sodium bicarbonate solution,then water followed by brine. The solution was taken to dryness and theresulting solid crystallized twice from methylene chloridemethanol togive 2.72 g. of 2-butylamino-4,5-dianisylthiazole of melting point155-158 C.

Analysis.Calcd. for C H N O S: C, 68.44; H, 6.56; N, 7.60. Found: C,68.46; H, 6.87; N, 7.44.

EXAMPLE 3 Z-a'ecylamina-4,5-dianisylthiazole A solution of 2.16 g. ofdecylthiourea and 3.35 g. of u-bIOIIIOdCSOXYaDlSOlH in 50 ml. of ethanolwas heated at reflux for 5 hours. The mixture was allowed to cool,treated wtih an equal volume of saturated aqueous sodium bicarbonatesolution and the diluted with water, whereupon a solid separated. Theprecipitated solid was collected on a filter, dried and recrystallizedtwice from Skellysolve B hexanes to give 3.90 g. of 2-decylamino-4,5-dianisylthiazole of melting point 79-82 C.

Analysis.--Calcd. for C27H36N2O2SI C, 71.64; H, 8.02; N, 6.19. Found: C,71.72; H, 8.27; N, 6.26.

EXAMPLE 4 Z-allylamin-4,5-dianisylthiaz0le A solution of 1.16 g. ofallylthiourea and 3.35 g. of a-bromodesoxyanisoin in 100 ml. of ethanolwas heated at reflux for a period of 4.5 hours. To this mixture wasadded 5 g. of solid sodium bicarbonate and the mixture was thereupontaken to dryness. The residue was suspended in water and the solidcollected on a filter. The solid was then recrystallized twice fromaqueous methanol to give 2.94 g. of 2-allylamino-4,S-dianisylthiazole ofmelting point 128-l31 C.

EXAMPLE 5 2-(6-chl0r0benzylamin0) -4,5-dianisylthiazole A solution of2.01 g. of p-chlorobenzylthiourea and 3.35 g. of a-bromodesoxyanisoin in50 ml. of acetonitrile was heated at reflux for a period of 2 hours. Themixture was then evaporated to dryness in vacuo and the resultingresidue was dissolved in ether and aqueous sodium bicarbonate solution.The organic layer was washed with water and brine and taken to dryness.The residual solid was chromatographed over 300 ml. of Florisil(anhydrous magnesium silicate), the column being eluted with 300'- ml.fractions consisting of and 25% acetone, balance Skellysolve B hexanes.Those fractions yielding residues with a melting point above 180 C. werecombined and recrystallized from acetonitrile to give 2.75 g. of2-(pchlorobenzylamino)-4,5-dianisylthiazole of melting point 182-185 C.

Analysis.Calcd. for C H CIN O S: C, 65.97; H, 4.84; N, 6.41. Found: C,66.07; H, 4.95; N, 6.44.

EXAMPLE 6 2-phenylamina-4,5-dianisylthiaz0le A solution of 1.52 g. ofphenylthiourea and 3.35 g. of wbromodesoxyanisoin in 50 ml. of ethanolwas heated at reflux for 2 hours. The hot mixture was then diluted withan equal volume of water which caused a solid to separate on cooling.This solid was recrystallized once from aqueous methanol to give 3.13 g.of 2-phenylamino-4,5- dianisylthiazole of melting point 175178 C.

Analysis.Calcd. for C H N O S: C, 71.11; H, 5.19; N, 7.21. Found: C,70.88; H, 5.28; N, 6.93.

EXAMPLE 7 2- (p-methoxyph'enylamino) -4,5-dianisy lthiazole A mixture of1.82 g. of p-methoxyphenylthiourea and 3.35 g. of a-bromodesoxyanisoinin 50 m1. of ethanol was heated at reflux for 1.5 hours. The mixture wastaken to dryness and the resulting residue was dissolved in methylenechloride. This solution was washed with aqueous sodium bicarbonatesolution and brine and taken again to dryness. The residual solid wasrecrystallized twice from aqueous acetone to give 2.8 g. of2-(p-methoxyphenylamino) 4,5 dianisylthiazole of melting point 182-185.5 C. v

Analysis.-Calcd. for C H N O S: C, 68.87; H, 5.30; N, 6.70. Found: C,68.74; H, 5.29; N, 6.59.

EXAMPLE 8 2- p-carbethoxyph enylaminv) -4,5-dianisylth iazolc A solutionof 2.0 g. of p-carbethoxyphenylthiourea and 3.0 g. ofa-bromodesoxyanisoin in 50 ml. of acetonitrile was heated at refluxtemperature for a period of 1.5 hours. The mixture was taken to drynessand the resulting residue was twice recrystallized from aqueous ethanolto give 3.41 g. of 2-(p-carbethoxyphenylamino)-4,5-dianisylthiazole ofmelting point 144148 C.

Analysis.Calcd. for C H N O S: C, 67.81; H, 5.25; N, 6.08. Found: C,68.08; H, 5.43; N, 6.04.

EXAMPLE 9 2-(p-carboxyphenylamino)-4,5-dianisylthiazole A mixture of 1g. of 2-(p-carbethoxyphenylamino)-4,5- dianisylthiazole and 2 ml. of 50%aqueous sodium hydroxide solution in 50 ml. of ethanol was heated atreflux for a period of 2 hours. The bulk of the solvent was thereuponremoved in vacuo and the residue was dispersed in 500 m1. of water. Thedispersion was washed with ether and the aqueous layer was acidified.The precipitated solid was collected by filtration and the productthusobtained was recrystallized from aqueous acetic acid. A total of0.62 g. of 2(p-carboxyphenylamino)4,5- dianisylthiazole of melting point278282 C. (dec.) was obtained.

Analysis.--Calcd. for C H N O S: C, 66.65; H. 4.66; N, 6.48. Found: C,66.61; H, 4.91; N, 6.53.

EXAMPLE 1O 2-acetylamin0-4,5-dianisylthiazole To a solution of 2 g. of2-amino-4,5-dianisylthiazole, in 50 ml. of tetrahydrofuran containing 1ml. of pyridine, was added 0.51 g. of acetyl chloride. After standing atroom temperature (about 25 C.) for 7 hours the mixture was distilled invacuo to give a concentrate to which were added ether and aqueous sodiumbicarbonate solution. The resulting solid was collected on a filter.This solid was recrystallized twice from aqueous methanol to give 0.96g. of 2-acetylamino-4,5-dianisylthiazole of melting point 193-195 C.

Analysis.Calcd. for C H N O S: C, 64.38; H, 5.12; N, 7.91. Found: C,64.57; H, 5.38; N, 8.11.

EXAMPLE 11 2-benzoylamino-4,5-dianisylthiazole Benzoyl chloride (0.9 g.)was added over a period of 10 minutes to a solution of 2.0 g. of2-amino-4,5-dianisylthiazole in 1 ml. of pyridine and 50 ml. oftetrahydrofuran. At the end of 4 hours of standing, the mixture wasdiluted with ether and water. The organic layer was washed with water,followed by 3 portions of 50 ml. each of cold 2.5 N hydrochloric acid.The acid extracts were combined and basified with dilute sodiumhydroxide solution to give 0.73 g. of recovered starting material,2-amino-4,S-dianisylthiazole of melting point 208210 C. The washedorganic layer was taken to dryness and the residue was chromatographedover 200 ml.

of Florisil (anhydrous magnesium silicate). The column was eluted withZOO-ml. fractions of 90% Skellysolve B hexanes and 10% acetone. Thefractions which showed a single spot by thin layer chromatography,namely fractions 612, were combined and evaporated to give 1.56 g. of2-benzoylamino-4,S-dianisylthiazole.

AnalySiS.-Calcd. for C24H20N203Si C, H, N, 6.73. Found: C, 69.46; H,5.01; N, 6.43.

EXAMPLE 12 2-(p-methoxybenzoylamin0) -4,5-dianisylthiazle A solution of2.0 g. of 2-amino-4,S-dianisylthiazole, 1.1 g. of anisoyl chloride and 1ml. of pyridine in 50 ml. of tetrahydrofuran was allowed to standovernight. The bulk of the solvent was then removed by distillation invacuo and the residue was dissolved in ether and aqueous sodiumbicarbonate solution. The organic layer was washed with water and brineand taken to dryness. The resulting residue was treated with a smallamount of ether and the solid collected on a filter. The solid was 0.39g. of crude starting material, namely 2-amino-4,5-dianisylthiazole. Thefiltrate was taken to dryness to give a gummy residue Which waschromatographed over 200- ml. of Florisil (anhydrous magnesiumsilicate), using as eluant a mixture consisting of 85% Skellysolve Bhexanes and 15% acetone, and collecting 200 ml. fractions. Thosefractions which crystallized on trituration with methanol were combinedand evaporated and thereupon twice recrystallized from methylenechloride-methanol to give 1.24 g. of2-(p-methoxybenzoylamino)-4,5-dianisylthiazole as a methanol solvate;melting point 85-88 C. (eflervescence).

Analysis.-Calcd. for C H N O S- /2CH OH: C, 67.71; H, 5.57; N, 6.49.Found: C, 67.20; H, 5.07; N, 6.52.

The above solvate was heated at 50 C. and 0.1 mm. pressure for 48 hoursto obtain Z-(p-methoxybenzoylamino) -4,5-dianisylthiazole.

EXAMPLE 13 2-methylamin0'-4,5 -d ianisyl thiazol e In the manner givenin Example I, methylthiourea was reacted with ot-bromodesoxyanisoin, inethanol at reflux temperature, to giveZ-rnethylamino-4,5-dianisylthiazole.

EXAMPLE 14 2-elhylamin0-4,5-dianisylthiazole In the manner given inExample 1, ethylthiourea was reacted with u-bromodesoxyanisoin, inethanol at reflux temperature, to giveZ-ethylamino-4,5-dianisylthiazole.

EXAMPLE 15 2-pr0pyIamin0-4,5-dianisylthiazole In the manner given inExample 1, propylthiourea was reacted with OL-bI'OmOdCSOXYaHISOiH, inethanol at reflux temperature, to give2-propylamino-4,S-dianisylthiazole.

EXAMPLE 16 2-penty[amino-4,5-dianisylihiazole In the manner given inExample 1, pentylthiourea was reacted with a-bromodesoxyanisoin, inethanol at reflux temperature, to give2-pentylamino-4,S-dianisylthiazole.

EXAMPLE 17 2-hexylamino-4,5-dianisylthiazole In the manner given inExample 1, hexylthiourea was reacted with tx-bromodesoxyanisoin, inethanol at reflux temperature, to give2-hexylamino-4,S-dianisylthiazole.

EXAMPLE 18 2-0ctyIamin0-4,5-dianisylthiazole In the manner given inExample 1, octylthiourea was reacted with a-brornodesoxyanisoin, inethanol at reflux temperature, to give2-octylamino-4,5-dianisylthiazole.

EXAMPLE 19 2-(Z-lzexenyl)amino-4,S-dianisylthiazole In the manner givenin Example 1, (Z-heXenyDthiQurea Was reacted with a-bromodesoxyanisoin,in ethanol at reflux temperature, to give2-(2-hexenyl)amino-4,5-dianisylthiazole.

EXAMPLE 20 Z-methallylaminc-4,5-dianisylthiazole In the manner given inExample 1, methallylthiourea Was reacted with a-bromodesoxyanisoin, inethanol at reflux temperature, to give2-methallylamino-4,S-dianisylthiazole.

EXAMPLE 21 2-cr0ty[amino-4,5-dianisylthiazole In the manner given inExample 1, crotylthiourea was reacted with a-bromodesoxyanisoin, inethanol at reflux temperature, to give2-crotylamino-4,S-dianisylthiazole.

EXAMPLE 22 2-isopropylamin0-4,5-dianisylthiazole In the manner given inExample 1, isopropylthiourea was reacted with a-bromodesoxyanisoin, inethanol at reflux temperature, to give2-isopropylamino-4,5-dianisylthiazole.

EXAMPLE 23 2-(Z-methyl-Z-butenyl)amin0-4,5-dianisylthiaz0le In themanner given in Example 1, (2-methyl-2-butenyl) thiourea was reactedwith a-bromodesoxyanisoin, in ethanol at reflux temperature, to give2-(2-methyl-2-butenyl) amino-4,5-dianisylthiazole.

EXAMPLE 24 Z-(p-bromobenzylamino) -4,5-diani.sylthiaz0le In the mannergiven in Example 1, p-bromobenzylthiourea was reacted withot-bromodesoxyanisoin, in ethanol at reflux temperature, to give2-(p-bromobenzylamino)-4,5- dianisylthiazole.

EXAMPLE 25 2- (p-fluorobenzlamino)-4,5-dianisylzhiaz0le In the mannergiven in Example 1, p-fiuorobenzylthiourea was reacted witha-bromodesoxyanisoin, in ethanol at reflux temperature, to give2-(p-fluorobenzylamino)-4,5- dianisylthiazole.

EXAMPLE 26 2-(o-chlorobenzylamino)-4,5-dianisylthiaz0le In the mannergiven in Example 1, o-chlorobenzylthiourea was reacted witha-bromodesoxyanisoin, in ethanol at reflux temperature, to give2-(o-chlorobenzylamino)- 4,5-dianisylthiazole.

EXAMPLE 28 Z-(m-ethoxybenzylamino) -4,5-dianisylthiaz0le In the mannergiven in Example 1, m-ethoxybenzylthiourea was reacted witha-bromodesoxyanisoin, in ethanol at reflux temperature, to give2-(m-ethoxybenzylamino)- 4,5-dianisylthiazole. 1

EXAMPLE 29 2-(p-propoxybenzylamino)-4,5-dianisylthiaz0le In the mannergiven in Example 1, p-propoxybenzylthiourea was reacted withu-bromodesoxyanisoin, in ethanol at reflux temperature, to giveZ-(p-propoxybenzylamino) -4,5-dianisylthi'azole.

EXAMPLE 3O Z-(p-fluorophenylamino) -4,5-dianisylthiazole In the mannergiven in Example 1, p-fluorophenylthiourea was reacted withot-bromodesoxyanisoin, in ethanol at reflux temperature, to give2-(p-fluorophenylamino)- 4,5-dianisylthiazole.

EXAMPLE 31 2-(o-bromophenylamino)-4,5-dianisyltlziaz0le In the mannergiven in Example 1, o-bromophenylthiourea was reacted withot-bl'OIIlOdCSOXYflIliSOiIl, in ethanol at reflux temperature, to give2-(o-bromophenylamino)-4,5- dianisylthiazole.

EXAMPLE 32 2-(p-carbopropoxyphenylamina)-4,5-dianisylthiazole In themanner given in Example 1, p-carbopropoxyphenylthiourea was reacted witha-bromodesoxyanisoin, in ethanol at reflux temperature, to giveZ-(p-carbopropoxyphenylamino) -4,5-dianisylthiazole.

In the manner given in Example 1, other 2-substituted-4,5-dianisylthiazoles are obtained by reacting a selected substitutedthiourea wlith u-bromodesoxyanisoin, preferably in solution and at thetemperature of reflux of the reaction mixture. Representative compounds,thus obtained, include: 2-heptylamino-4,S-dianisylthiazole, 2-nonylamino-4,S-d-ianisylthiazole, 2-isobutylamino-4,5-dianisylthiazole,2-(2-ethylallylarnino)-4,5-dianisylthiazo1e,2-(o-fluorobenzylamino)-4,5-dianisylthiazole,Z-(o-iodobenzylamino)-4,5-dianisylthiazole, 2-(o-methoxybenzylamino)-4,5-dianisylthiazole, 2- (m-propoxybenzylamino 4,5-dianisy1thiazole,2-benzylamino-4,S-dianisylthiazole,2-(m-ethoxyphenylamino)-4,5-dianisylthiazole,2-(o-carbomethoxyphenylamino)-4,5-dianisylthiazole,Z-(m-carbopropoxyphenylamino)-4,5-dianisylthiazole,2-(p-methylphenylamino-4,S-dianisylthiazole, 2 (o propylphenylamino)-4,5-dianisylthiazole, Z-(m-methylbenzylamino) 4,5-dianisylthiazole, 2(p isopropylbenzylamino)-4,5- dianisylthiazole and the like.

EXAMPLE 33 Z-undecanoylamin 4,5-dianisylthiazole In the manner given inExample 10, 2-amin0-4,5-dianisylthiazole was reacted with undecanoylchloride to give 2-undecanoyl-amino-4,5-dianisylthiazole.

EXAMPLE 34 2-octanoylamino-4,5-dianisylthiazole In the manner given inExample 10, 2-amino-4,5-dianisylthiazole was reacted with octanoylchloride to give 2-actanoylamino-4,S-dianisylthfiazole.

anisylthiazole was reacted with valeryl chloride to give2-valerylamino-4,S-dianisylthiazole.

EXAMPLE 36 2-(0-chl0r0benz0yl)-4,5-dianisylflziaz0le In the manner givenin Example 10, 2-amino-4,5-dianisylthiazole was reacted witho-chlorobenzoyl chloride to give2-(o-chlorobenzoylamino)-4,5dianisylthiazole.

EXAMPLE 37 2-(p-ethylbenzoylamino)-4,5-dianisylthiaz0le In the mannergiven in Example 10, 2-amino-4,5-dianisylthiazole was reacted withp-ethylbenzoyl chloride to give2-(p-ethylbenzoylamino)-4,5-dianisylthiazole.

EXAMPLE 38 2-(p-fluorobenzoylamino)-4,5-dianisylthiaz0le In the mannergiven in Example 10, 2-amino-4,5-dianisylthiazole was reacted withp-fluorobenzoyl chloride to give2-(p-fluorobenzoylamino)-4,5-dianisylthiazole.

EXAMPLE 39 2-is0butyrylamino-4,5-dianisylthiazole In the manner given inExample 10, 2-amino-4,5-dianisylthiazole was reacted with isobutyrylchloride to give 2-isobutyrylamino-4,S-dianisylthiazole.

EXAMPLE 40 2- (p-carbetlzoxybenzoylamin0)-4,5-dianisylthiaz0le In themanner given in Example 10, 2-amino-4,5-dianisylthiazole was reactedwith p-carbethoxybenzoyl chloride to give2-(p-carbethoxybenzoylamino)-4,5-dianisylthiazole.

In the manner given in Example 10, other Z-acylamino-4,5-dianisylthiazoles can be obtained by reacting Z-amino-4,5-dianisylthiazole with a selected acyl bromide or chloride, or ananhydnide of an organic carboxylic acid, particularly of an alkanoicacid having from 2 to 11 carbon atoms, inclusive, or of a benzoic acidor substituted benzoic acid. Representative compounds thus obtained include: 2-propionylamino-4,S-dianisylthiazole,2-butyrylamino-4,S-dianisylthiazole,2-hexanoylamino-4,5-dianisylthiazole,2-heptanoylamino-4,5-dianisylthiazo1e,Z-nonanoylamino-4,5-dianisylthiazole, Z-decanoylaminoLS-dianisylthiazole, 2-(m-iodobenzoylarnino)-4,5-dianisylthiazole, 2-o-ethylbenzoylamino -4,5-dianisylthiazole, 2-p-propoxybenzoylamino)-4,5-dianisylthiazole, 2 (pisopropoxybenzoylamino)-4,5-dianisylthiazole,2-(m-isopropylbenzoylamino)-4,5-dianisylth-iazole,2-(o-bromobenzoylamino)-4,5-dianisylthiazole, and the like.

EXAMPLE 41 Z-melhyl-4,5-dianisylthiaz0le A mixture of 1.62 g. ofthioacetamide and 7.25 g. of abromodesoxyanisoin in 100 ml. ofacetonitrole was heated at reflux temperature for a period of 2 hours.The reaction mixture was evaporated in vacuo to give a residue which wasshaken with a mixture of ether and aqueous sodium bicarbonate solution.The organic layer was separated, washed with water and brine andevaporated to dryness. The solid which remained was recrystallized fromSkellysolve B hexanes to give 6.17 g. of 2-methyl-4,5-dianisylthiazoleof melting point 7579 C. Another recrystallization from Skellysolve B'hexanes gave pure Z-methyl-4,5-dianisylthiazole of melting point 77 .5-C.

Analysis.-Calcd. for C H NO S: C, 69.42; H, 5.50; N, 4.50. Found: C,69.03; H, 5.50; N, 4.22.

EXAMPLE 42 2-ethyl-4,5-dianisylthiazole In the manner given in Example41, thiopropionamide and a-bromodesoxyanisoin were reacted to give2-ethyl- 4,5-dianisylthiazole.

EXAMPLE 43 Z-propyl-4,5-dianisylthiaz0le In the manner given in Example41, thiobutyramide and u-bromodesoxyanisoin were reacted to give2-propyl-4,5- dianisylthiazole.

EXAMPLE 44 2-butyl-4,5-dianisylthiazole In the manner given in Example41, thiovaleramide and a-bromodesoxyanisoin were reacted to give2-butyl-4,S- dianisylthiazole.

EXAMPLE 45 2-benzyl-4,5-dianisylthiazole In the manner given in Example41, thiophenylacetamide and a-bromodesoxyanisoin were reacted to give 2-benzyl-4,S-dianisylthiazole.

EXAMPLE 46 Methyl 4,5-dianisyl-2-thiazoleacetate A solution of 2 g. of2-methyl-4,5-dianisylthiazole in 50 ml. of tetrahydrofuran was cooled inan acetone-solid carbon dioxide bath. T this solution was added 4.3 ml.of 1.49 N butyllithium in pentane. The red mixture was stirred for aperiod of 10 minutes in a nitrogen atmosphere and transferred undernitrogen pressure to a prepared slush consisting of 100 ml. of powderedsolid carbon dioxide and 20 ml. of tetrahydrofuran. The carbon dioxidewas allowed to evaporate and the mixture taken to dryness. The solidresidue was suspended in ether and the solid collected on a filter. Thesolid (lithium 4,5-dianisyl- Z-thiazoleacetate) was dissolved in icewater and the solution was made acidic with '64 ml. of 0.1 Nhydrochloric acid (with cooling). The mixture was then quickly extractedwith ether. The ether layer was separated, washed with cold water andbrine and percolated through sodium sulfate. This solution, containing4,5-dianisyl-2-thiazoleacetic acid, was treated with etherealdiazomethane (prepared from 5 g. of N-nitro-N-nitroso-methylguanidine),then allowed to stand for minutes and evaporated to dryness to give anoily residue. This residue was chromatographed over 200 ml. of Florisil,taking ZOO-ml. fractions with an eluant consisting of 95% Skellysolve Bhexanes and 5% acetone. Fractions 9 to 22 were combined andrecrystallized twice from ether-Skellysolve B hexanes to give 1.20 g. ofmethyl 4,5-dianisyl-2-thiazo1eacetate of melting point 66-70 C.

Analysis.Calcd. for C H NO S: C, 65.02; H, 5.18; N, 3.79. Found: C,65.01; H, 5.62; N, 3.92.

EXAMPLE 47 Ethyl 4,5-dianisyl-Z-thiazoleacetate In the manner given inExample 46, 4,5-dianisyl-2-thiazoleacetic acid was reacted withdiazoethane to give ethyl 4,5-dianisyl-Z-thiazoleacetate.

EXAMPLE 48 Methyl 4,5-dianz'syl-a-methyI-Z-Ihiazoleacetate In the mannergiven in Example 46, a solution of Z-ethyl-4,5-dianisylthiazole wastreated with butyllithium in pentane to give2-(l-lithiumethyl)-4,5-dianisylthiazole; this compound was treated withcarbon dioxide to obtain 4,S-dianisyl-a-methyl-2-thiazoleacetic acid;and, this acid was treated with diazomethane to obtain methyl4,5-dianisyl-ot-methyl-2-thiazoleacetate.

EXAMPLE 49 Methyl 4,5-dianis'yI-u-ethyI-Z-thiazoleacetate In the mannergiven in Example 46, a solution of Z-propyl-4,5-dianisylthiazole wastreated with butyllithium in pentane to give2-(l-lithiumpropyl)-4,5-dianisylthiazole; this compound was treated withcarbon dioxide to obtain 4,S-dianisyl-a-ethyl-2-thiazoleacetic acid;and, this acid was treated with diazomethane to obtain methyl4,5-dianisyl-a-ethyl-Z-thiazoleacetate.

EXAMPLE 50 Ethyl 4,S-dianisyl-u-pr0pyl-2-thiazoleacetate In the mannergiven in Example 46, a solution of 2-butyl-4,S-dianisylthiazole wastreated with butyllithium in pentane to give2-(l-lithiumbutyl)-4,5-dianisylthiazole; this compound was treated withcarbon dioxide to give 4,S-dianisyl-a-propyl-2-thiazoleactic acid; and,this acid was treated with diazoethane to give ethyl4,5-dianisyl-apropyl-Z-thiazoleacetate.

EXAMPLE 51 Methyl 4,5-dianz'syl-u-phenyl-Z-thiazoleacetate wherein R isselected from the group consisting of hydrogen; alkyl having from 1 to10 carbon atoms, inclusive; lower alkenyl having from 3 to 6 carbonatoms, inclusive; phenyl of the formula:

III

in which X X and X are substituents selected from the group consistingof hydrogen, halogen, alkyl and alkoxy having from 1 to 3 carbon atoms,inclusive, carboxy, and carbalkoxy having from 2 to 4 carbon atoms,inclusive; benzyl in which the phenyl group is defined as above; andacyl of the formula R'CO in which R is selected from the groupconsisting of alkyl having from 1 to 10 carbon atoms, inclusive, andphenyl defined as above.

. 2-amino-4,S-dianisylthiazole.

. 2-butylamino-4,S-dianisylthiazole.

. 2-decylamino-4,S-dianisylthiazole.

. 2-allylamino-4,S-dianisylthiazole.

. 2-(p-chlorobenzylamino)-4,5-dianisylthiazole.

. 2-phenylamino-4,S-dianisylthiazole.

. 2-(p-methoxyphenylamino)-4,5-dianisylthiazole.

2-(p-carbethoxyphenylamino)-4,5-dianisylthiazole. 10.2-(p-carboxyphenylamino)-4,5-dianisylthiazole.

11. 2-acetylamino-4,S-dianisylthiazole.

12. 2-benzoylamino-4,S-dianisylthiazole.

13. 2- (p-methoxybenzoylamino -4,5-dianisylthiazole.

References Cited UNITED STATES PATENTS 2,639,285 5/ 1953 Sonogrn et a1260-306.8

ALEX MAZEL, Primary Examiner R. I. GALLAGHER, Assistant Examiner US. Cl.X.R. 260302, 999

5, 58,5 jv y 9 969 Patent No. Dated Inventor(s) Dan l i Lednicer It iscertified that error appears in the -above--identified patent and thatsaid Letters Patent are hereby corrected as shown below:

CoILimn I ine 28, for "diseasees" read diseases I ine &4, for "ehtyi"read fithyl Column 7, I ine 11, for "$01 id crysta I I ized" read soI idwas crystallized Iine 23, for "treated wtih" read treated with I ine 24,for "and the di Iuted" read and then di Iuted I ine 45 for "2- (6-" read2- (p- Coiumn 8, I ine +1, for "2 (p-carboxyphenyIamiri0) I,5-" read 2-(pwarboxyphenyi amino)- I,5- CoIumn 9, I ine 41, for "Example I readExample 1 Column 10, Iine 50, for "diansyI" read dianisyi CoIumn 11,Iine 39, for "phenyIamino- I,5" read phenyIamino)- I,5 line 55, for"2-actanoyi" read 2-octanoyI Column 12, line 4}, for "acetonitroie" readacetonitri le Column 14, Ii ne 3, for "2-thiazoleactic" read2-thiazoleacetic was W9 aauzn azmgafll

